The interaction of the T cell receptor (TCR) with its specific ligand, peptide-MHC, is only one component of the events required for the activation of antigen-specific T cells. The primary goals of our studies are to characterize cell surface antigens (co-receptors) and their soluble or cell associated ligands (counter-receptors) which play critical roles in cell-cell interaction and in the interaction of T cells with their environment. We have concentrated our efforts in a number of distinct areas: 1) We have previously demonstrated that the human CD59 antigen and its murine homologue, Ly-6, play important roles in the T cell activation cascade. We have engineered soluble forms of both CD59 and Ly-6 and demonstrated that these fusion proteins interact with both soluble and membrane bound IgM. These studies raise the possibility that Ly-6/CD59 may play critical roles in T-B cell interaction. 2) We have shown that the newly characterized cytokine, IL10, inhibits T cell activation by acting on macrophages and not other types of accessory (AC) cells. These studies suggest that IL10 inhibits the costimulatory function of AC by preventing the induction of a critical membrane molecule needed for macrophage-T cell interaction. Studies are in progress to identify this target molecule. 3) One model of immunologic tolerance involves the induction of peripheral T cell anergy by the injection of adult mice with Staphylococcal enterotoxin B (SEB). We have reversed the tolerant state in SEB-treated mice by a concomitant infection with the nematode, Nippostrongylus brasiliensis (Nb), which results in the generation of SEB-specific IL4 producing T cells. These results have important implications for the induction of autoimmune diseases following infectious diseases. 4) In order to extend our studies to the responses of human T lymphocytes to infectious agents, we have utilized T and B lymphocyte deficient SCID mice and reconstituted them with leukocytes from patients with the tuberculoid form of leprosy. This model is being developed to analyze the requirements for the induction of a primary immune response to Mycobacterium leprae by human cells in the SCID environment.